The invention relates to substituted arylsulphonamide-substituted benzimidazoles having tryptase-inhibiting activity, methods for preparing such compounds and their use for the treatment of inflammatory and/or allergic diseases.
Benzimidazole derivatives are known from the prior art as active substances having valuable pharmaceutical properties. Thus, International Patent Application WO 98/37075 discloses, in addition to other bicyclic heterocycles, benzimidazoles which can be used to good effect for the prevention and treatment of venous and arterial thrombotic diseases, on the basis of their thrombin-inhibiting activity.
In contrast to the use of benzimidazole derivatives as described above and known from the prior art, the aim of the present invention is to prepare new tryptase-inhibitors which can be used, on the basis of their tryptase-inhibiting properties, for the prevention and treatment of inflammatory and/or allergic diseases.
The present invention provides new benzimidazoles of general formula (I) 
wherein:
R1 denotes a group selected from among C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkinyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C1-C4-alkoxy, CF3, phenoxy, COOH, halogen, xe2x80x94CO(C1-C4-alkoxy), xe2x80x94CONH2, xe2x80x94COxe2x80x94NH(C1-C4-alkyl), xe2x80x94COxe2x80x94N(C1-C4-alkyl)2, xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2 or C1-C4-alkoxy-phenoxy, or
a C3-C8-cycloalkyl optionally linked via a C1-C4-alkylene bridge, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C1-C4-alkoxy, carboxy, halogen, C1-C4-alkoxycarbonyl or CF3, or
phenyl-C1-C4-alkyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C1-C4-alkoxy, carboxy, halogen, C1-C4-alkoxycarbonyl or CF3, or
a 5- or 6-membered, saturated or unsaturated heterocyclic group linked directly or via a C1-C4-alkylene bridge, which may contain one or two hetero atoms selected from among oxygen, nitrogen or sulphur and which may optionally be substituted by C1-C4-alkyl or benzyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2;
R3 denotes a group selected from among phenyl, benzyl, naphthyl, furan, quinolyl, isoquinolyl, benzofuranyl, thienyl and benzothienyl, which is mono-, di- or trisubstituted in each case by one or more of the groups selected from among C1-C4-alkyl, C1-C4-alkoxy, halogen, C1-C4-alkyl-halogen, xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, NO2, hydroxy, xe2x80x94CF3, xe2x80x94NHCOxe2x80x94C1-C4-alkyl, xe2x80x94COOH, xe2x80x94COO(C1-C4-alkyl), xe2x80x94CONH2, xe2x80x94CONH(C1-C4-alkyl), xe2x80x94CON(C1-C4-alkyl)2, xe2x80x94CONH(C1-C4-alkyl)xe2x80x94COO(C1-C4-alkyl) and phenyl-C1-C6-alkyl, wherein the substituent phenyl-C1-C6-alkyl may in turn be substituted by a group selected from among C1-C6-alkoxy, hydroxy, halogen, CF3 and C1-C6-alkyl;
R4 denotes hydrogen, a C1-C6-alkyl group, which may be mono- or disubstituted by one or two of the groups xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
a 5-, 6- or 7-membered, saturated or unsaturated heterocyclic group linked directly or via a C1-C4-alkylene bridge or via a C1-C4-alkylene-CO bridge which may optionally contain one, two or three hetero atoms selected from among oxygen, nitrogen or sulphur and which may optionally be substituted by C1-C4-alkyl, benzyl or pyridyl;
C3-C8-cycloalkyl, which may be mono- or disubstituted by one or two of the groups xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
phenyl, benzyl or phenylethyl, which may be mono- or disubstituted at the phenyl ring by one or two of the groups xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94C1-C4-alkyl-NH2, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, ps optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
The compounds of formula I of the invention have a tryptase-inhibiting effect and may be used according to the invention for the prevention and treatment of diseases in which tryptase-inhibitors may develop a therapeutic effect.
Preferred are those compounds of formula I wherein:
R1 denotes C1-C6-alkyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C1-C4-alkoxy, CF3, phenoxy, COOH, halogen, xe2x80x94CO(C1-C4-alkoxy), xe2x80x94CONH2, xe2x80x94COxe2x80x94NH(C1-C4-alkyl), xe2x80x94COxe2x80x94N(C1-C4-alkyl)2, xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2 or C1-C4-alkoxy-phenoxy, or
a C3-C8-cycloalkyl optionally linked via a C1-C4-alkylene bridge, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C1-C4-alkoxy, carboxy, halogen, C1-C4-alkoxycarbonyl or CF3, or
phenyl-C1-C4-alkyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C1-C4-alkoxy, carboxy, halogen, C1-C4-alkoxycarbonyl or CF3, or
a 5- or 6-membered, saturated or unsaturated heterocyclic group linked directly or via a C1-C4-alkylene bridge, which may contain one or two hetero atoms selected from among oxygen, nitrogen or sulphur and which may optionally be substituted by C1-C4-alkyl or benzyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2;
R3 denotes a group selected from among phenyl, benzyl, naphthyl, quinolyl, isoquinolyl, thienyl and benzothienyl which is mono-, di- or trisubstituted in each case by one or more of the groups selected from among C1-C4-alkyl, C1-C4-alkoxy, halogen, xe2x80x94C1-C4-alkyl-halogen, xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, NO2, hydroxy, xe2x80x94CF3, xe2x80x94NHCOxe2x80x94C1-C4-alkyl, xe2x80x94COOH, xe2x80x94COO(C1-C4-alkyl), xe2x80x94CONH2, xe2x80x94CONH(C1-C4-alkyl), xe2x80x94CON(C1-C4-alkyl)2, xe2x80x94CONH(C1-C4-alkyl)-COO(C1-C4-alkyl) and phenyl-C1-C4-alkyl, wherein the substituent phenyl-C1-C4-alkyl may in turn be substituted by a group selected from among C1-C4-alkoxy, hydroxy, halogen, CF3 and C1-C4-alkyl;
R4 denotes hydrogen, a C1-C6-alkyl group, which may be mono- or disubstituted by one or two of the groups xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
a 5-, 6- or 7-membered, saturated or unsaturated heterocyclic group linked directly or via a C1-C4-alkylene bridge or via a C1-C4-alkylene-CO bridge, which may optionally contain one, two or three hetero atoms selected from among oxygen, nitrogen or sulphur and may optionally be substituted by C1-C4-alkyl, benzyl or pyridyl;
C3-C8-cycloalkyl, which may be mono- or disubstituted by one or two of the groups xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
phenyl, benzyl or phenylethyl, which may be mono- or disubstituted at the phenyl ring by one or two of the groups xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, C1-C4-alkyl-NH2, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2,
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
More preferred are those compounds of formula I wherein:
R1 denotes C1-C5-alkyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C1-C4-alkoxy, CF3, phenoxy, COOH, xe2x80x94CO(C1-C4-alkoxy), xe2x80x94CONH2, xe2x80x94COxe2x80x94NH(C1-C4-alkyl), xe2x80x94COxe2x80x94N(C1-C4-alkyl)2 or C1-C4-alkoxy-phenoxy, or
a C3-C8-cycloalkyl optionally linked via a C1-C4-alkylene bridge, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C1-C4-alkoxy, carboxy, halogen, C1-C4-alkoxycarbonyl or CF3, or
phenyl-C1-C4-alkyl, which may optionally be mono-, di- or trisubstituted by one or more of the groups hydroxy, C1-C4-alkoxy, carboxy, C1-C4-alkoxycarbonyl or CF3, or
a 5- or 6-membered, saturated or unsaturated heterocyclic group linked directly or via a C1-C4-alkylene bridge, which may contain one or two hetero atoms selected from among oxygen, nitrogen or sulphur and may optionally be substituted by C1-C4-alkyl or benzyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2;
R3 denotes a group selected from among phenyl, benzyl, benzothienyl, quinolyl, isoquinolyl and naphthyl, which is mono-, di- or trisubstituted in each case by one or more of the groups selected from among C1-C4-alkyl, C1-C4-alkoxy, halogen, CF3, xe2x80x94C1-C4-alkyl-halogen, xe2x80x94NH2, xe2x80x94NH(C1-C4-alkyl), xe2x80x94N(C1-C4-alkyl)2, NO2, hydroxy, xe2x80x94CF3, xe2x80x94NHCOxe2x80x94C1-C4-alkyl, xe2x80x94COOH, xe2x80x94COO(C1-C4-alkyl), xe2x80x94CONH2, xe2x80x94CONH(C1-C4-alkyl), xe2x80x94CON(C1-C4-alkyl)2, xe2x80x94C(CH3)2-phenyl (wherein the phenyl group may be substituted by one or more halogen atoms or hydroxy groups) and xe2x80x94CONH(C1-C4-alkyl)-COO(C1-C4-alkyl);
R4 denotes a C1-C6-alkyl group, which may be mono- or disubstituted by one or two of the groups xe2x80x94NH2, xe2x80x94NHmethyl, xe2x80x94N(methyl)2, xe2x80x94NHethyl, xe2x80x94N(ethyl)2, xe2x80x94NH(n-propyl), xe2x80x94N(n-propyl)2, xe2x80x94NH(iso-propyl), xe2x80x94N(iso-propyl)2, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
a 5-, 6- or 7-membered, saturated or unsaturated nitrogen heterocyclic group linked directly or via a C1-C4-alkylene bridge or via a C1-C4-alkylene-CO bridge, which may optionally contain one or two other hetero atoms selected from among oxygen, nitrogen or sulphur and may optionally be substituted by C1-C4-alkyl, benzyl or pyridyl;
cyclopropyl, cyclopentyl or cyclohexyl, each of which is mono- or disubstituted by one or two of the groups xe2x80x94NH2, xe2x80x94NHmethyl, xe2x80x94N(methyl)2, xe2x80x94NHethyl, xe2x80x94N(ethyl)2, xe2x80x94NH(n-propyl), xe2x80x94N(n-propyl)2, xe2x80x94NH(iso-propyl), xe2x80x94N(iso-propyl)2, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
unsubstituted benzyl or phenyl, benzyl or phenylethyl which are mono- or disubstituted at the phenyl ring by one or two of the groups xe2x80x94NH2, xe2x80x94NHmethyl, xe2x80x94N(methyl)2, xe2x80x94NHethyl, xe2x80x94N(ethyl)2, xe2x80x94NH(n-propyl), xe2x80x94N(n-propyl)2, xe2x80x94NH(iso-propyl), xe2x80x94N(iso-propyl)2, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2,
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Even more preferred substituted benzimidazole derivatives of general formula (I) are those wherein:
R1 denotes methyl, ethyl, propyl, butyl or pentyl, each of which may be substituted by one of the groups hydroxy, methoxy, ethoxy, propoxy, CF3, phenoxy, COOH, CONH2, CONHMe or methoxy-phenoxy, or
benzyl, phenylethyl or phenylpropyl, which may be mono- or disubstituted at the phenyl ring by one or two of the groups hydroxy, methoxy, ethoxy, carboxy, methoxycarbonyl, ethoxycarbonyl or CF3, or
a 5- or 6-membered, saturated or unsaturated heterocyclic group linked directly or via a C1-C4-alkylene bridge, which may contain one or two hetero atoms selected from among oxygen or nitrogen and may optionally be substituted by methyl, ethyl, propyl or benzyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2;
R3 denotes phenyl, benzyl or naphthyl, each of which is mono- or disubstituted by one or two groups selected from among methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, fluorine, chlorine, bromine, iodine, xe2x80x94CF3, xe2x80x94NH2, xe2x80x94NHmethyl, xe2x80x94NHethyl, xe2x80x94Nmethyl2, xe2x80x94Nethyl2, NO2, xe2x80x94NHCO-methyl, xe2x80x94NHCO-ethyl, xe2x80x94COOH, xe2x80x94COOmethyl, xe2x80x94COOethyl, xe2x80x94CONH2, xe2x80x94CONHmethyl, xe2x80x94CONHethyl, xe2x80x94CONmethyl2, xe2x80x94CONethyl2, xe2x80x94CONHxe2x80x94CH2xe2x80x94COOH, xe2x80x94CONHxe2x80x94CH2xe2x80x94COOmethyl, xe2x80x94CONHxe2x80x94CH2xe2x80x94COOethyl, xe2x80x94CONHxe2x80x94CH2CH2xe2x80x94COOH, xe2x80x94CONHxe2x80x94CH2CH2xe2x80x94COOmethyl, xe2x80x94C(CH3)2-phenyl (wherein the phenyl group may be substituted by one or more halogen atoms or hydroxy groups) and xe2x80x94CONHxe2x80x94CH2CH2xe2x80x94COOethyl;
R4 denotes a group selected from among ethyl, propyl, butyl, pentyl and hexyl, each of which is mono- or disubstituted by one or two of the groups xe2x80x94NH2, xe2x80x94NHmethyl, xe2x80x94N(methyl)2, xe2x80x94NHethyl, xe2x80x94N(ethyl)2, xe2x80x94NH(n-propyl), xe2x80x94N(n-propy1)2, xe2x80x94NH(iso-propyl), xe2x80x94N(iso-propyl)2, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
a 5-, 6- or 7-membered, saturated or unsaturated nitrogen-heterocyclic group linked directly or via a C1-C4-alkylene bridge, which may optionally contain one or two other hetero atoms selected from among oxygen or nitrogen and may optionally be substituted by methyl, ethyl, propyl or benzyl, or
cyclopentyl or cyclohexyl, each of which may be mono- or disubstituted by one or two of the groups xe2x80x94NH2, xe2x80x94NHmethyl, xe2x80x94N(methyl)2, xe2x80x94NHethyl, xe2x80x94N(ethyl)2, xe2x80x94NH(n-propyl), xe2x80x94N(n-propyl)2, xe2x80x94NH(iso-propyl), xe2x80x94N(iso-propyl)2, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2, or
unsubstituted benzyl or benzyl or phenylethyl which are mono- or disubstituted at the phenyl ring by one or two of the groups xe2x80x94NH2, xe2x80x94NHmethyl, xe2x80x94N(methyl)2, xe2x80x94NHethyl, xe2x80x94N(ethyl)2, xe2x80x94NH(n-propyl), xe2x80x94N(n-propyl)2, xe2x80x94NH(iso-propyl), xe2x80x94N(iso-propyl)2, xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2,
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Still more preferred are substituted benzimidazole derivatives of general formula (I), wherein:
R1 denotes methyl, ethyl, propyl, butyl or pentyl, preferably methyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2, preferably xe2x80x94C(xe2x95x90NH)NH2;
R3 denotes phenyl or naphthyl, each of which is substituted by one or two groups selected from among methyl, ethyl, tert.-butyl, methoxy, ethoxy, fluorine, chlorine, bromine, CF3, xe2x80x94NH2, xe2x80x94NHmethyl, xe2x80x94NHethyl, xe2x80x94Nmethyl2, xe2x80x94Nethyl2, NO2, xe2x80x94NHCO-methyl, xe2x80x94NHCO-ethyl, xe2x80x94COOH, xe2x80x94COOmethyl, xe2x80x94COOethyl, xe2x80x94CONH2, xe2x80x94CONHmethyl, xe2x80x94CONHethyl, xe2x80x94CONmethyl2, xe2x80x94CONethyl2, xe2x80x94CONHxe2x80x94CH2xe2x80x94COOH, xe2x80x94CONHxe2x80x94CH2xe2x80x94COOmethyl, xe2x80x94C(CH3)2-phenyl (wherein the phenyl group may be substituted by one or more halogen atoms or hydroxy groups) and xe2x80x94CONHxe2x80x94CH2xe2x80x94COOethyl;
R4 denotes ethyl or propyl, each of which is substituted by one of the groups xe2x80x94NH2, xe2x80x94N(methyl)2, xe2x80x94N(ethyl)2, xe2x80x94N(n-propyl)2 or xe2x80x94C(xe2x95x90NH)NH2, or
a 5-, 6- or 7-membered, saturated or unsaturated nitrogen-heterocyclic group linked directly or via a methylene or ethylene bridge, which may contain an oxygen as a further heteroatom and may optionally be substituted by methyl, ethyl, propyl or benzyl, or
cyclopentyl or cyclohexyl, each of which is substituted by one of the groups xe2x80x94NH2, xe2x80x94N(methyl)2, xe2x80x94N(ethyl)2, xe2x80x94N(n-propyl)2 or xe2x80x94C(xe2x95x90NH)NH2, or
benzyl, which may be substituted at the phenyl ring by one of the groups xe2x80x94NH2, xe2x80x94N(methyl)2, xe2x80x94N(ethyl)2, xe2x80x94N(n-propyl)2 or xe2x80x94C(xe2x95x90NH)NH2,
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Even more greatly preferred are substituted benzimidazole derivatives of general formula (I), wherein:
R1 denotes methyl, ethyl, propyl, butyl or pentyl, preferably methyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2, preferably xe2x80x94C(xe2x95x90NH)NH2;
R3 denotes phenyl which is substituted by one or two groups selected from among methyl, ethyl, tert-butyl, methoxy, ethoxy, fluorine, chlorine, bromine, CF3, and/or a group selected from among xe2x80x94NH2, xe2x80x94NHmethyl, xe2x80x94NHethyl, xe2x80x94Nmethyl2, xe2x80x94Nethyl2, NO2, xe2x80x94NHCO-methyl, xe2x80x94NHCO-ethyl, xe2x80x94COOH, xe2x80x94COOmethyl, xe2x80x94COOethyl, xe2x80x94CONH2, xe2x80x94CONHmethyl, xe2x80x94CONHethyl, xe2x80x94CONmethyl2, xe2x80x94CONethyl2, xe2x80x94CONHxe2x80x94CH2xe2x80x94COOH, xe2x80x94CONHxe2x80x94CH2xe2x80x94COOmethyl, xe2x80x94C(CH3)2-phenyl, (wherein the phenyl group may be substituted by one or more halogen atoms or hydroxy groups) and xe2x80x94CONHxe2x80x94CH2xe2x80x94COOethyl, or naphthyl which is substituted by xe2x80x94Nmethyl2 or chlorine;
R4 denotes benzyl, pyridylmethyl, dimethylaminoethyl, diethylaminoethyl, dimethylaminopropyl or diethylaminopropyl,
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Still more greatly preferred are substituted benzimidazole derivatives of general formula (I), wherein:
R1 denotes methyl, ethyl or propyl, preferably methyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2, preferably xe2x80x94C(xe2x95x90NH)NH2;
R3 denotes phenyl substituted by one or two groups selected from among methyl, ethyl, tert-butyl, methoxy, ethoxy, fluorine, chlorine, bromine, CF3, and/or a group selected from among xe2x80x94NH2, xe2x80x94NHmethyl, xe2x80x94NHethyl, xe2x80x94Nmethyl2, xe2x80x94Nethyl2, NO2, xe2x80x94NHCO-methyl, xe2x80x94NHCO-ethyl, xe2x80x94COOH, xe2x80x94COOmethyl, xe2x80x94COOethyl, xe2x80x94CONH2, xe2x80x94CONHmethyl, xe2x80x94CONHethyl, xe2x80x94CONmethyl2, xe2x80x94CONethyl2, xe2x80x94CONHxe2x80x94CH2xe2x80x94COOH, xe2x80x94CONHxe2x80x94CH2xe2x80x94COOmethyl, xe2x80x94C(CH3)2-phenyl, (wherein the phenyl group may be substituted by one or more halogen atoms or hydroxy groups), and xe2x80x94CONHxe2x80x94CH2xe2x80x94COOethyl, or naphthyl which is substituted by xe2x80x94Nmethyl2 or chlorine;
R4 denotes dimethylaminoethyl or diethylaminoethyl, optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Penultimately preferred are substituted benzimidazole derivatives of general formula (I), wherein:
R1 denotes methyl;
R2 denotes xe2x80x94C(xe2x95x90NH)NH2 or xe2x80x94CH2xe2x80x94NH2, preferably xe2x80x94C(xe2x95x90NH)NH2;
R3 denotes phenyl substituted by one or two groups selected from among methyl, tert-butyl, methoxy, chlorine, bromine, CF3, and/or a group selected from among xe2x80x94NH2, NO2, xe2x80x94NHCO-methyl, xe2x80x94COOethyl, xe2x80x94CONHxe2x80x94CH2xe2x80x94COOH, xe2x80x94C(CH3)2-phenyl (wherein the phenyl group may be substituted by one or more halogen atoms or hydroxy groups), and xe2x80x94CONHxe2x80x94CH2xe2x80x94COOethyl, or naphthyl which is substituted by xe2x80x94Nmethyl2 or chlorine;
R4 denotes benzyl or diethylaminoethyl,
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Ultimately preferred and exemplary of the invention are the following specific compounds:
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(4-ethoxycarbonyl-benzenesulphonamide)-hydrochloride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(dansylamide)-dihydrochloride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(3-bromo-benzenesulphonamide)-hydrochloride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(4-nitro-benzenesulphonamide)-hydrochloride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(3-methoxy-benzenesulphonamide)-hydrochloride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(3-methyl-benzenesulphonamide)-hydrochloride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(3-chloro-benzenesulphonamide)-hydrochloride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(4-amino-benzenesulphonamide)-tetrahydrochloride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(4-acetylamino-benzenesulphonamide)
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(4-chloro-benzenesulphonamide)
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-[3,5-di-(trifluoromethyl)-benzenesulphonamide] dihydrochloride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(6-hydroxy-naphth-2-ylsulphonamide) dihydrochloride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(3-trifluormethyl-benzenesulphonamide)dihydrochloride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-[3-(1-methyl-1-phenyl-ethyl)-benzenesulphonamide]dihydrochloride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-aminoethyl-(dansylamide)dihydrochloride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(4-tert-butyl-benzenesulphonamide)dihydrochloride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-pyrid-3-ylmethyl-(dansylamide)dihydrochioride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(8-chloro-naphth-1-ylsulphonamide)dihydrochloride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-pyrid-4-ylmethyl-(dansylamide)dihydrochloride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-benzyl-(4-tert-butyl-benzenesulphonamide)dihydrochloride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(3-nitro-benzenesulphonamide)dihydrochloride
N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(3-amino-benzenesulphonamide)dihydrochloride.
In addition to the abovementioned compounds of general formula (I) the present invention also relates to compounds which are only converted into the therapeutically effective compounds of general formula (I) by the body after being taken by the patient, on the basis of a functionality which can be cleaved in vivo. Such compounds are known as prodrugs. According to another aspect the invention therefore relates to prodrugs of general formula (II) 
wherein
R1 and R3 may be as hereinbefore defined and
R4 may be as hereinbefore defined or may denote C1-C4-alkyl which is substituted by a group selected from among xe2x80x94C(xe2x95x90NOH)NH2, xe2x80x94C(xe2x95x90NCOOxe2x80x94C1-C12-alkyl)NH2 or xe2x80x94C(xe2x95x90NCOOxe2x80x94C1-C8-alkyl-phenyl)NH2;
R5 denotes hydroxy, xe2x80x94COOxe2x80x94C1-C12-alkyl, xe2x80x94CO-phenyl, xe2x80x94CO-pyridyl or xe2x80x94COOxe2x80x94C1-C8-alkyl-phenyl, whilst in the abovementioned group the phenyl ring may be substituted in each case by C1-C4-alkyl, C1-C4-alkoxy, OH, halogen or CF3,
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Preferred are prodrugs of general formula (II) wherein
R1 and R3 may be as hereinbefore defined and
R4 may be as hereinbefore defined or denotes C1-C4-alkyl which is substituted by a group selected from among xe2x80x94C(xe2x95x90NOH)NH2, xe2x80x94C(xe2x95x90NCOOxe2x80x94C1-C6-alkyl)NH2 or xe2x80x94C(xe2x95x90NCOOxe2x80x94C1-C6-alkyl-phenyl)NH2;
R5 denotes hydroxy, xe2x80x94COOxe2x80x94C1-C6-alkyl, xe2x80x94CO-phenyl, xe2x80x94CO-pyridyl or xe2x80x94COOxe2x80x94C1-C6-alkyl-phenyl, whilst in the abovementioned group the phenyl ring may be substituted in each case by C1-C4-alkyl, C1-C4-alkoxy, OH, halogen or CF3,
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
Particularly preferred are prodrugs of general formula (II), wherein
R1, R3 and R4 may be as hereinbefore defined and
R5 may denote hydroxy, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, butyloxycarbonyl, benzoyl, benzyloxycarbonyl or nicotinoyl,
optionally in the form of their tautomers, racemates, enantiomers, diastereomers and mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
The term alkyl groups (including those which are part of other groups), unless otherwise stated, denotes branched and unbranched alkyl groups with 1 to 12 carbon atoms, preferably 1-8 carbon atoms, most preferably 1 to 6 carbon atoms. Examples are: methyl, ethyl, propyl, butyl, pentyl, hexyl, etc. Unless otherwise stated, the above terms propyl, butyl, pentyl or hexyl also include all the possible isomeric forms. For example, the term propyl also includes the two isomeric groups n-propyl and iso-propyl, the term butyl includes n-butyl, iso-butyl, sec. butyl and tert.-butyl, the term pentyl includes iso-pentyl, neopentyl, etc. In some cases common abbreviations are also used to denote the abovementioned alkyl groups, such as Me for methyl, Et for ethyl etc.
The term alkenyl groups (including those which are part of other groups) denotes branched and unbranched alkenyl groups having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, provided that they have at least one double bond, for example the alkyl groups mentioned above as well, provided that they have at least one double bond, such as for example vinyl (provided that no unstable enamines or enolethers are formed), propenyl, iso-propenyl, butenyl, pentenyl and hexenyl.
The term alkinyl groups (including those which are part of other groups) denotes alkinyl groups having 2 to 6 carbon atoms, provided that they have at least one triple bond, e.g. ethinyl, propargyl, butinyl, pentinyl and hexinyl.
The term halogen generally denotes fluorine, chlorine, bromine or iodine.
Examples of cycloalkyl groups with 3-8 carbon atoms according to the invention are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Examples of 5-, 6- or 7-membered, saturated or unsaturated heterocycles which may contain nitrogen, oxygen or sulphur as heteroatoms, include, unless otherwise stated in the definitions, furan, tetrahydrofuran, tetrahydrofuranon, xcex3-butyrolactone, xcex1-pyran, xcex3-pyran, dioxolan, tetrahydropyran, dioxane, thiophene, dihydrothiophene, thiolan, dithiolan, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine, triazole, tetrazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, tetrazine, morpholine, thiomorpholine, diazepan, oxazole, isoxazole, oxazine, thiazole, isothiazole, thiadiazole, oxadiazole and pyrazolidine, wherein the heterocyclic group may be substituted as stated in the definitions.
Unless otherwise specified, the two alkyl groups in the dialkylaminosubstituents xe2x80x94N(C1-C4-alkyl)2 may be identical or different.
xe2x80x9cxe2x95x90Oxe2x80x9d denotes an oxygen atom linked via a double bond.
As already mentioned, the compounds of general formula (I) according to the invention are effective as tryptase inhibitors. A further aspect of the present invention is therefore directed to the use of the compounds of general formula (I) as hereinbefore defined for preparing a pharmaceutical composition for the prevention and/or treatment of diseases in which tryptase inhibitors may be of therapeutic value.
It is preferred according to the invention to use compounds of general formula (I) for the purpose mentioned above, for preparing a pharmaceutical composition for the prevention and/or treatment of inflammatory and/or allergic diseases. It is particularly preferable to use the compounds of general formula (I) as mentioned above for preparing a pharmaceutical composition for the prevention and/or treatment of bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria, allergic otitis, allergic gastro-intestinal disorders, Crohn""s disease, ulcerative colitis, anaphylactic shock, septic shock, shock lung (ARDS) and arthritis.
It is also advantageous to use the compounds of general formula (I) as mentioned above for preparing a pharmaceutical composition for the prevention and/or treatment of fibroses such as lung fibrosis, fibrosing alveolitis and scarring, collagenoses such as lupus erythematodes and sclerodermia as well as arteriosclerosis, psoriasis and neoplasm.
The substituted benzimidazole derivatives of formula (I) as well as the prodrugs of general formula (II) may be obtained by various methods of synthesis. Possible approaches based on and using conventional methods of chemical synthesis are hereinafter described by way of example. Diagram 1 shows one possible method of synthesising the basic benzimidazole structure of the compounds according to the invention,
In a first step (Diagram 1, step i) the 3-nitro-4-halo-anilines (1) are reacted to form the sulphonamides (2). 
For this purpose the compounds (1) are taken up in a suitable organic, anhydrous solvent and combined with the desired arylsulphonic acid chloride, optionally in the presence of an organic base, while cooling. Suitable organic solvents may be halogenated hydrocarbons such as dichloromethane or chloroform as well as solvents selected from among dioxan, tetrahydrofuran, dimethylformamide, acetonitrile and pyridine. It is preferred according to the invention to use pyridine or pyridine mixed with dichloromethane or chloroform as solvent. If an organic base is added, amines such as triethylamine, diisopropylethylamine, N-methylmorpholine or pyridine are primarily used. The arylsulphonic acid chloride is preferably added at temperatures below ambient temperature, particularly between xe2x88x9240xc2x0 C. and 20xc2x0 C., most preferably at xe2x88x9220xc2x0 C. to 10xc2x0 C. After the reaction has ended (about 0.5-2 h) the mixture is worked up by conventional methods. The compounds (2) may optionally be purified by crystallisation from nonpolar organic solvents such as, for example, diethylether, petroleum ether, optionally mixed with ethyl acetate.
In a second step (Diagram 1, step ii) the sulphonamides (2) are reacted to form the compounds (3). The aminolysis of the compounds (2) with the primary amines R1xe2x80x94NH2 is carried out in suitable organic solvents such as for example dimethylsulphoxide, N,N-dimethylformamide, N-methylpyrrolidone, acetone or optionally in water or alcohols at ambient temperature or in a temperature range from 30-80xc2x0 C., preferably 40-50xc2x0 C.
The reduction of the nitro groups to form the compounds (4, Diagram 1, step iii) is carried out for example by catalytic hydrogenation in organic solvents such as for example methanol, ethanol, isopropanol, tetrahydroflran, optionally also in admixture with dimethylformamide, ethylacetate, dioxan or acetic acid, at elevated hydrogen pressure or at normal pressure at temperatures between 0-50xc2x0 C., preferably at 20-40xc2x0 C. Suitable catalysts are conventional hydrogenation catalysts. Palladium and Raney nickel are preferred. According to the invention, palladium is preferred. Palladium on charcoal (5%) is particularly preferred as the catalyst. An alternative method of reducing the nitro compounds (3) envisages the use of reduction agents such as Na2S2O4 or SnCl2. This reaction is carried out in protic, water-miscible organic solvents such as short-chained alcohols (methanol, ethanol, isopropanol) or in a mixture of the abovementioned solvents with water, optionally with acetic acid, dimethylformamide or ethylacetate. The reaction is normally carried out at elevated temperature, preferably by refluxing the solvent or solvent mixture in question. After the reaction of the starting compounds (3) is complete, the mixture is worked up in the usual way. The compounds (4) may be purified for example by crystallisation from nonpolar organic solvents such as diethylether, petroleum ether, optionally mixed with ethyl acetate.
In a fourth step (Diagram 1, step iv) cyclisation to form the benzimidazoles (5) is carried out by reacting the sulphonamide derivatives (4) with p-cyanophenylpropionic acid in the presence of dehydrating reagents. The reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxan. Suitable dehydrating agents include for example isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilan, phosphorus oxychloride, thionylchloride, trimethylchlorosilan, phosphorus trichloride, phosphorus pentoxide, ethyl 1,2-dihydro-2-ethoxy-quinoline-1-carboxylate (EEDQ), i-propyl 1,2-dihydro-2-i-propyloxy-quinoline-1-carboxylate (IIDQ), N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclo-hexylcarbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-dicyclohexylcar-bodiimide/1-hydroxy-benzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole, N,Nxe2x80x2-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride. It may be appropriate to add a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine. The reaction is usually carried out at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 20 and 120xc2x0 C.
An alternative method of obtaining the compounds (5) is shown by way of example in Diagram 2. 
Starting from the 2-halo-5-nitro-anilines (6) aminolysis may first be carried out to obtain the diaminonitrobenzenes (7) according to Diagram 2 (step v). Reacting the compounds (7) with p-cyanophenylpropionic acid leads to the nitro-benzimidazoles (8, step vi), which can be reductively converted into the amino-benzimidazoles (9) (step vii, Diagram 2). The compounds (5) may be obtained from the amino-benzimidazoles (9) by reaction with the corresponding arylsulphonic acid chlorides (Diagram 2, step viii). The synthesis outlined in Diagram 2 may be carried out experimentally analogously to the procedure described for steps i-iv (Diagram 1). Step v is carried out analogously to the method according to step ii, step vi analogously to the method according to step iv, step vii analogously to the method described for step ii and, finally, step viii according to the experimental method in step i.
Starting from the benzimidazoles (5) which may be obtained according to Diagrams 1 and 2, the intermediates of formula (III) (cf. Diagram 3) are obtained by reaction with the compounds R4xe2x80x94Nu, where Nu denotes a nucleofugic leaving group such as for example chlorine, bromine, iodine, methanesulphonate, methyltriflate, p-toluenesulphonate etc. 
Alternatively, the intermediates (III) may be obtained from the compounds (5) by reductive amination by reacting with correspondingly substituted ketones or aldehydes under reductive conditions.
In order to react the compounds (5) with R4xe2x80x94Nu according to step x the following procedure is used. A compound (5) is dissolved in a polar solvent, such as dimethylformamide, dimethylactamide, methylene chloride, tetrahydrofliran, preferably dimethylformamide and most preferably anhydrous, possibly absolute dimethylformamide. The solution thus obtained is combined with a base and the corresponding alkylating agent R4xe2x80x94Nu. The base used may be an alkali or alkaline earth metal carbonate of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate and preferably potassium carbonate. It is also possible to use the alkali or alkaline earth metal hydroxides of lithium, sodium, potassium, magnesium, calcium, but preferably sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide in alcohol or water. The reaction mixture is stirred for 0.5-8 h, preferably 1-4 h at elevated temperature, preferably at 50-120xc2x0 C., particularly at the reflux temperature of the solvent used. After the reaction is complete the mixture is worked up in the usual way and the crude product obtained is purified by crystallisation or chromatography on silica gel.
If the intermediates (III) are obtained from the compounds (5) by reductive amination, the following procedure is used. The compound (5) is dissolved in a suitable solvent such as for example dichloromethane, dichloroethane, methanol, ethanol, tetrahydrofuran or toluene, and at between 0-60xc2x0 C., preferably at 20-40xc2x0 C., the corresponding carbonyl compound is added in the presence of an acid, preferably a carboxylic acid, most preferably a short-chained carboxylic acid, particularly acetic acid. Then a suitable reduction agent is added. Suitable reduction agents which may be used according to the invention are Na[HB(OAc)3], Na[BH3CN], NaBH4, Pd/Cxe2x80x94H2, preferably Na[HB(OAc)3]. After working up in the usual way the product is purified by crystallisation or chromatography on silica gel.
According to step xi the compounds of general formula (I) according to the invention may be obtained from the intermediates (III). Various methods may be used to prepare the compounds of general formula (I) according to the invention wherein R2 denotes xe2x80x94C(xe2x95x90NH)NH2.
A compound of general formula (I) is obtained for example by treating a compound of general formula (III) with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzylalcohol optionally mixed with another organic solvent such as for example chloroform, nitrobenzene or toluene in the presence of an acid such as hydrochloric acid or by reacting a corresponding amide with a trialkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxan at temperatures between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C. and subsequent aminolysis with alcoholic ammonia solution, for example. Alternatively, the compounds of general formula (I) may be obtained by reacting a compound of general formula (III) with sulphur nucleophiles such as e.g. hydrogen sulphide, ammonium or sodium sulphide, sodium hydrogen sulphide, carbon disulphide, thioacetamide or bistrimethylsilylthioether, optionally in the presence of bases such as triethylamine, ammonia, sodium hydride or sodium alkoxide in solvents such as methanol, ethanol, water, tetrahydrofrran, pyridine, dimethylformamide or 1,3-dimethyl-imidazolidin-2-one at 20-100xc2x0 C., and subsequent treatment with a suitable methylating agent such as e.g. methyliodide or dimethylsulphate in a solvent such as acetonitrile or acetone at temperatures between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C., and subsequent treatment with ammonia, ammonium carbonate or ammonium chloride in a suitable alcohol, such as for example methanol, ethanol, isopropanol etc. at temperatures between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C.
Moreover, the compounds of general formula (I) according to the invention may be obtained by treating a compound of general formula (III) with lithiumhexamethyl disilazide in a suitable organic solvent such as e.g. tetrahydrofuran at temperatures between xe2x88x9220 and 50xc2x0 C., but preferably at 0-20xc2x0 C. and subsequently hydrolysing with dilute hydrochloric acid at 0-5xc2x0 C.
Another alternative method of obtaining compounds of general formula (I) is by treating a compound of general formula (III) with ammonium chloride and trimethylaluminium in a suitable organic solvent such as e.g. toluene at temperatures between 20 and 150xc2x0 C., but preferably at 110xc2x0 C.
Compounds of general formula (I) wherein R2 denotes xe2x80x94CH2xe2x80x94NH2 may be obtained from the intermediates (III) for example by catalytic hydrogenation on Raney nickel. These reactions are preferably carried out in protic organic solvents such as short-chained alcohols (methanol, ethynol or isopropanol) at temperatures between 10-40xc2x0 C., preferably at 20-30xc2x0 C. under normal pressure.
A compound of general formula (II) is obtained for example by treating a compound of general formula (III, Diagram 3, step xii) with hydroxylamine in the presence of carbonates or alkoxides of alkali or alkaline earth metals in solvents such as methanol, ethanol, n-propanol or isopropanol optionally in admixture with dioxan or tetrahydrofuran. The alkoxides may be prepared from the respective alkali metals or metal hydrides and the corresponding alcohol. The reaction is preferably carried out at 20-100xc2x0 C., most preferably at the boiling temperature of the solvent used.
Compounds of general formula (II) may alternatively be obtained by treating a compound of general formula (III) with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzylalcohol in the presence of an acid such as hydrochloric acid or by reacting a corresponding amide with a trialkyloxonium salt such as triethyloxonium-tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofaran or dioxan at temperatures between xe2x88x9210 and 50xc2x0 C., but preferably at 0-20xc2x0 C. and subsequently treating with hydroxylamine in the presence of bases in a suitable alcohol, such as methanol, ethanol, isopropanol etc. at temperatures between xe2x88x9210 and 50xc2x0 C., but preferably at 0-200xc2x0 C.
A compound of general formula (I) is obtained for example by treating a compound of general formula (II, Diagram 3, step xiii) with hydrogen in the presence of hydrogenation catalysts such as Raney nickel or rhodium/aluminium oxide in water or methanol optionally with the addition of acids such as hydrochloric acid or methanesulphonic acid or by treating with hydrogen in the presence of palladium/charcoal in acetic acid/acetic anhydride at 20-50xc2x0 C. and 1-5 bar hydrogen pressure, preferably at ambient temperature and normal pressure.
The acyl- or alkoxycarbonyl prodrugs (II) of the compound of general formula (I) are obtained by reacting the compounds of general formula (I) with the corresponding acid chlorides in the presence of bases such as e.g. triethylamine, N-methylmorpholine, diethylisopropylamine or DBU in a suitable solvent such as methylene chloride, chloroform, tetrahydrofuran, acetonitrile, dimethylformamide or dimethylsulphoxide.
In accordance with their central role in the synthesis of the compounds of general formula (I) according to the invention as well as the synthesis of the prodrugs of general formula (II), a further aspect of the present invention is directed to the intermediates of general formula (III). 
wherein the groups R1, R3 and R4 may be as hereinbefore defined. The compounds of general formula (III) are valuable intermediates for preparing the benzimidazole derivatives of general formula (I) according to the invention as well as the prodrugs of general formula (II) according to the invention.
Procedures by way of example for preparing the compounds according to the invention will be described in more detail hereinafter. The Examples which follow serve solely as a detailed illustration without restricting the subject matter of the invention.